Composition for treating ApoL1-related diseases

Abstract

In some embodiments of the present invention, the present invention relates to the field of compositions and / or pharmaceutical compositions comprising one or more biologically active compounds, and to methods of using such compositions and / or pharmaceutical compositions, such as for treating an ApoL1-associated disease or disorder in a subject.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 021,222, filed on May 7, 2020, entitled “Compositions for the Treatment of APOL1-Related Diseases,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates generally to the field of compositions comprising, inter alia, one or more quinazolinedione derivatives, and to methods of using such compositions, such as for treating a disease or condition. Background Art

[0004] Apolipoprotein L1 (ApoL1) is a minor apolipoprotein component of high-density lipoprotein (HDL) that is synthesized in the liver and in many other tissues including the pancreas, kidneys and brain. It is well known that ApoL1 plays a role in innate immunity by protecting against infection by the Trypanosoma parasite. Recently, it has been reported that high-frequency mutant variants of ApoL1, designated G1 and G2 (in contrast to the original version designated G0), are highly correlated with kidney disease in people of African descent. Many African Americans also have ApoL1 risk alleles and a high prevalence of ApoL1-related kidney disease. Since the discovery of the potential risks of G1 and G2 ApoL1 mutants, researchers have been trying to elucidate the cellular mechanisms of ApoL1 toxicity in order to develop potential candidate drugs for the treatment or prevention of ApoL1-related kidney disease. Summary of the Invention

[0005] The following embodiments and aspects thereof are described and illustrated in terms of systems, tools, and methods that are meant to be exemplary and illustrative, not limiting in scope.

[0006] In one aspect of the invention, there are compounds comprising one or more of the following compounds:

[0007]

[0008] or a salt thereof.

[0009] In another aspect of the present invention, there is a pharmaceutical composition comprising: (i) a compound of the present invention, a pharmaceutically acceptable salt thereof, or both; and (ii) a pharmaceutically acceptable carrier.

[0010] In another aspect of the present invention, there is a pharmaceutical composition comprising:

[0011]

[0012] or a compound represented by Formula 1A:

[0013]

[0014] wherein each R, R1 and R2 independently comprises alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, C1-C10 alkyl, substituted C1-C10 alkyl, or is absent; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently comprises methylene, heteroatom, -OR, -NRR, -SR, cyano, alkyl, carboxyl derivative, nitro, sulfonate, sulfonyl, or hydrogen; each X independently comprises methylene, heteroatom, or is absent; represents a single bond or a double bond; and each n is between 0 and 10, or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable carrier for inhibiting or reducing ApoL1-related cytotoxicity.

[0015] In one embodiment, the compound is represented by Formula 1C:

[0016]

[0017] In one embodiment, the compound comprises

[0018]

[0019] In one embodiment, the compound is represented by Formula 2:

[0020]

[0021] wherein R3 represents a substituent independently comprising at least one of the following or is absent: C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, hydroxy, amino, thiol, cyano, carboxylic acid derivatives, nitro, guanidine, aryl, heteroaryl, benzyl, alkaryl, cycloalkyl, heterocyclic, heteroatom, hydrogen.

[0022] In one embodiment, the compound is represented by Formula 3:

[0023]

[0024] In one embodiment, the compound is represented by Formula 4:

[0025]

[0026] Wherein: n is between 0 and 5; each R3 represents independently including the following substituents or does not exist:

[0027]

[0028] wherein A represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or is absent; and each R4 represents a substituent independently comprising hydrogen, C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, nitro, hydroxyl, thiol, amino, cyano, and carboxyl derivatives, or any combination thereof.

[0029] In one embodiment, each R3 is independently selected from the group consisting of:

[0030]

[0031] In one embodiment, the compound is represented by any one of Formulas 7A to 7C:

[0032] Formula 7A:

[0033]

[0034] Formula 7B:

[0035]

[0036] Formula 7C:

[0037]

[0038] wherein each X2 is independently selected from the group consisting of methylene, heteroatom, alkyl, halide, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, a bond and hydrogen or any combination thereof.

[0039] In one embodiment, each X 1 independently comprises a heteroatom, and each X is independently selected from the group consisting of: —N—, —NH, —O—, and —S—.

[0040] In one embodiment, the substituted C1-C10 alkyl group includes a substituent selected from the group consisting of halide, thiol, hydroxyl, amino, carboxyl derivatives, cyano, nitro, sulfonate, and sulfonyl, or any combination thereof.

[0041] In one embodiment, the compound includes any of the following:

[0042]

[0043] In one embodiment, the inhibition or reduction of ApoL1-related cytotoxicity comprises the prevention or treatment of ApoL1-related kidney disease.

[0044] In one embodiment, the ApoL1-associated cytotoxicity is ApoL1 mutant-associated cytotoxicity.

[0045] In another aspect of the present invention, there is a method for inhibiting or reducing ApoL1-associated cytotoxicity in a subject in need thereof, the method comprising administering a pharmaceutical composition comprising a compound represented by Formula 1:

[0046]

[0047] or a compound represented by Formula 1A:

[0048]

[0049] in:

[0050] each R, R1 and R2 independently comprise alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, C1-C10 alkyl, substituted C1-C10 alkyl, or are absent; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently comprises methylene, heteroatom, -OR, -NRR, -SR, cyano, alkyl, carboxyl derivative, nitro, sulfonate, sulfonyl, or hydrogen; each X independently comprises methylene, heteroatom, or are absent; represents a single bond or a double bond; and each n is between 0 and 10, or a pharmaceutically acceptable salt of the compound; and a pharmaceutically acceptable carrier, thereby inhibiting or reducing ApoL1-associated cytotoxicity in the subject.

[0051] In one embodiment, inhibiting or reducing ApoL1-associated cytotoxicity comprises preventing or treating ApoL1-associated kidney disease.

[0052] In one embodiment, the ApoL1-associated cytotoxicity is ApoL1 mutant-associated cytotoxicity.

[0053] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figures 1A-1C1 is a bar graph showing the viability of T-REx-293 cells after incubation with various concentrations of exemplary compounds of the invention for 16 hours versus untreated controls. Black bars represent cell counts for cells expressing ApoL1 G1 (activated by doxycycline). White bars represent cell counts for cells expressing wild-type ApoL1. Figure 1A : Incubated with various concentrations of compound 1 (0 μM, 0.08 μM, 0.156 μM, 0.3 μM, 0.6 μM, 1.25 μM, 2.5 μM, 5 μM and 10 μM). Figure 1B : Incubated with compound 3 at various concentrations (0 μM, 0.08 μM, 0.156 μM, 0.3 μM, 0.6 μM, 1.25 μM, 2.5 μM, 5 μM and 10 μM). Figure 1C : Incubated with various concentrations of compound 7 (0 μM, 0.156 μM, 0.313 μM, 0.625 μM, 1.25 μM, 2.5 μM, 5 μM and 10 μM).

[0055] Figure 2 : is a bar graph showing the viability of T-REx-293 cells after incubation with exemplary compounds of the invention (KS-1, KS-2, or KS-8 at a concentration of 10 μM) for 16 hours versus untreated cells (as a negative control). The Y-axis depicts cell counts. DETAILED DESCRIPTION

[0056] In one aspect of the invention disclosed herein, a compound, salt or derivative thereof is provided, wherein the compound is represented by Formula 1.2:

[0057] wherein each X independently comprises a methylene group, a heteroatom, or is absent; and each R′ independently comprises a (C0-C6)alkyl-aryl group, a (C0-C6)alkyl-heteroaryl group, a (C0-C6)alkyl-(C3-C8)cycloalkyl group, an optionally substituted C3-C8 heterocyclyl group, a halogen, -NO2, -CN, -OH, -CONH2, -CONR"2, -CNNR"2, -CSNR"2, -CONH-OH, -CONH-NH2, -NHCOR", -NHCSR", -NHCNR", -NC(=O)OR", -NC(=O)NR", -NC(=S)OR", -NC(=S)NR", -SO2R", -SOR", -SR", -SO2OR", -SON(R)2, -NHNR2, -NNR, C1-C 10 Haloalkyl, optionally substituted C1-C 10 Alkyl, -NH2, -NH(C1-C 10 Alkyl), -N(C1-C10 Alkyl)2, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, hydroxy (C1-C 10 Alkyl), hydroxyl (C1-C 10 Alkoxy), alkoxy (C1-C 10 Alkyl), alkoxy (C1-C 10 Alkoxy), C1-C 10 Alkyl-NR"2, C1-C 10 Alkyl-SR, -CONH(C1-C 10 Alkyl), -CON(C1-C 10 alkyl)2, -CO2H, -CO2R", -OCOR", -OCOR", -OC(=O)OR", -OC(=O)NR", -OC(=S)OR", -OC(=S)NR", including any combination thereof; and wherein R" is selected from optionally substituted C1-C 10 Alkyl and hydrogen.

[0058] In some embodiments, the heteroatoms are independently selected from the group consisting of O, N, NH, and S. In some embodiments, the heteroatom is N.

[0059] In some embodiments, the compounds of the present invention are represented by Formula 1.2A:

[0060] Or it can be expressed by Equation 1.3:

[0061] wherein X and R' are as described above.

[0062] In some embodiments, the compounds of the present invention are or include:

[0063] (also referred to herein as Compound 7), wherein the compound optionally includes any salt or any derivative thereof.

[0064] In another aspect of the present invention, there is provided a compound represented by Formula 1:

[0065] wherein each R, R1 and R2 independently comprises alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydrogen, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, optionally substituted C1-C10 alkyl, or is absent; or R1 and R2 are interconnected to form a cyclic ring; each X1 independently comprises methylene, heteroatom, -OR", -NR"R", -SR", cyano, alkyl, carboxyl derivatives, nitro, sulfonate, sulfonyl, or hydrogen; R" is as described herein, and each X independently comprises CH, CH2, heteroatom, or is absent; represents a single bond or a double bond; and each n is between 0 and 10.

[0066] In some embodiments, each n independently represents an integer ranging from 0 to 10, 0 to 1, 1 to 2, 2 to 4, 4 to 6, 6 to 10, including any ranges therebetween.

[0067] In some embodiments, the heteroatoms are independently selected from the group consisting of O, N, NH, and S. In some embodiments, the heteroatom is N.

[0068] In some embodiments, each of R1 and R2 independently comprises R' or H, wherein R' is as described herein. In some embodiments, each of R1 and R2 independently comprises optionally substituted C1-C10 alkyl, halo, sulfonate, sulfonyl, nitro, hydroxyl, thiol, amino, cyano, carboxyl derivatives, alkylhydroxyl, aminoalkyl, thiolalkyl, CONH2, -CONR"2, -CNNR"2, -CSNR"2, -CONH-OH, -CONH-NH2, -NHCOR", -NHCSR", -NHCNR", -NC(=O)OR", -NC(=O)NR", -NC(=S)OR", -NC(=S)NR", -CO2H, -CO2R", -OCOR", -OCOR", -OC(=O)OR", -OC(=O)NR", -OC(=S)OR", -OC(=S)NR", or H, including any combination or salt thereof.

[0069] In some embodiments, each of R1 and R2 independently comprises H or C1-C10 alkyl, which optionally comprises one or more substituents selected from the group consisting of: halo, sulfonate, sulfonyl, nitro, hydroxyl, sulfhydryl, amino, cyano, carboxyl derivatives, alkylhydroxyl, aminoalkyl, sulfhydrylalkyl, or any combination thereof. In some embodiments, each of R1 and R2 independently comprises H or C1-C10 alkyl optionally substituted with one or more R'. In some embodiments, each of R1 and R2 independently comprises alkyl, hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, or is absent.

[0070] In some embodiments, the cyclic ring is an aliphatic cycloalkyl, an aliphatic heterocyclic group, an aromatic ring, a heteroaromatic ring, or a combination thereof. In some embodiments, the cyclic ring is a fused ring. In some embodiments, the cyclic ring is a bicyclic ring. In some embodiments, the ring includes one or more substituents, wherein the substituents are as described herein.

[0071] In some embodiments, the compounds of the present invention are represented by any of the following:

[0072]

[0073] wherein X, X1, R, R1, R2 and n are as described above.

[0074] In some embodiments, the compounds of the present invention are represented by Formula 1C, wherein each R independently comprises a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; X is N or CH; and wherein X1 is O or OH. In some embodiments, is substituted by one or more (e.g., 1, 2, 3, 4) R's.

[0075] In some embodiments, the compounds of the present invention are represented by Formula 1D:

[0076] wherein each R1 independently comprises a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, hydrogen, a haloalkyl, a mercaptoalkyl, a heteroatom, a hydroxyalkyl, an aminoalkyl, a nitroalkyl, an alkyl sulfate, a substituted or unsubstituted C1-C10 alkyl, or any combination thereof; and wherein R1, R', n, and X are as described herein. In some embodiments, the compounds of the present invention are represented by Formula 1D, wherein each R1 is a substituted or unsubstituted C1-C10 alkyl, wherein n is independently 0 to 5 (e.g., selected from 0, 1, 2, and 3); and wherein each R' is a halogen or absent.

[0077] In some embodiments, the compounds of the present invention are or include:

[0078] Also referred to herein as Compound 1, optionally including any salt or any derivative thereof.

[0079] In some embodiments, the compounds of the present invention are represented by Formula 2:

[0080] wherein R3 represents a substituent independently comprising, or is absent, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, thiol, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, arylalkyl, cycloalkyl, heterocyclyl, hydrogen, and wherein X, X1, R, and n are as described above. In some embodiments, R3 represents a substituent independently comprising, or is absent, at least one of: C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, hydroxy, amino, thiol, cyano, carboxylic acid derivatives, nitro, guanidine, aryl, heteroaryl, benzyl, alkaryl, cycloalkyl, heterocyclyl, heteroatom, hydrogen.

[0081] In some embodiments, the compounds of the present invention are represented by any of the following:

[0082]

[0083] wherein X, X1, R, R1, R2, R3 and n are as described above.

[0084] In some embodiments, the compounds of the present invention are selected from Formulas 3A to 3D:

[0085] wherein X, X1, R, R3 and n are as described above.

[0086] In some embodiments, the compounds of the present invention are represented by any of the following:

[0087] wherein X, X1, R, R3 and n are as described above.

[0088] In some embodiments, R3 is hydrogen. In some embodiments, each R3 independently comprises any one of the following:

[0089] wherein the dashed line represents a single bond or a double bond; wherein each X2 independently comprises at least one of the following: methylene, heteroatom, alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, mercapto, cyano, carboxylic acid derivatives, nitro, guanidine, heteroatom, aryl, heteroaryl, benzyl, alkylaryl, cycloalkyl, heterocyclyl, bond or hydrogen; wherein each A independently represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring or is absent; and wherein X and n are as described above.

[0090] In some embodiments, the dashed line represents a single bond, and each X2 independently includes at least one of the following: alkyl, halo, alkoxy, hydroxy, amino, thioalkoxy, thiol, cyano, a carboxylic acid derivative, nitro, guanidine, a heteroatom, aryl, heteroaryl, benzyl, alkaryl, cycloalkyl, heterocyclyl, a bond, and hydrogen.

[0091] In some embodiments, the dotted line represents a double bond, and each X2 independently includes at least one of the following: methylene, heteroatom, cycloalkyl and heterocyclyl. In some embodiments, the dotted line represents a double bond, and each X2 independently includes a heteroatom. In some embodiments, X2 represents a bond.

[0092] In some embodiments, R3 comprises hydrogen or

[0093] wherein X is a heteroatom or absent; A represents an optionally substituted aliphatic (C3-C20) ring or an optionally substituted aromatic (C5-C20) ring; and wherein n is between 0 and 5.

[0094] In some embodiments, A represents an optionally substituted aliphatic (C5-C7) ring, an optionally substituted heterocyclic aliphatic (C5-C7) ring, an optionally substituted aromatic (C5-C6) ring, or an optionally substituted heteroaromatic (C5-C6) ring. In some embodiments, A represents an optionally substituted bicyclic aliphatic (C6-C15) ring, an optionally substituted bicyclic aromatic (C6-C15) ring, or an optionally substituted fused (C6-C15) ring. In some embodiments, A represents an optionally substituted aliphatic (C5-C7) ring or an optionally substituted aromatic (C5-C6) ring.

[0095] In some embodiments, the compounds of the present invention are represented by Formula 4:

[0096] wherein X1, R and R3 are as described above, n is between 0 and 5, and R4 is as described below.

[0097] In some embodiments, each X 1 independently represents a heteroatom or a methylene group. In some embodiments, the dashed bond is a double bond.

[0098] In some embodiments, R3 is hydrogen or

[0099] wherein X and R are as described above. In some embodiments, each X is independently selected from -NH, -O-, and -S- or is absent.

[0100] In some embodiments, R3 is hydrogen or

[0101] wherein X and A are as described above.

[0102] In some embodiments, R3 is hydrogen or

[0103] wherein R is as described above.

[0104] In some embodiments, R3 is hydrogen. In some embodiments, each R3 is independently selected from:

[0105] wherein R4 comprises any of the following: hydrogen, alkyl, C1-C10 branched alkyl, haloalkyl, mercaptoalkyl, heteroatom, hydroxyalkyl, aminoalkyl, nitroalkyl, alkyl sulfate, C1-C10 alkyl optionally comprising a substituent selected from the group consisting of halo, nitro, hydroxyl, mercapto, amino, cyano, carboxyl derivatives, alkylhydroxyl, aminoalkyl, mercaptoalkyl, or any combination thereof; and wherein X and X1 are as described above. In some embodiments, R3 represents one or more substituents. In some embodiments, each X1 is independently selected from N and CH. In some embodiments, each X is independently selected from the group consisting of -N-, -NH, -O-, and -S-.

[0106] In some embodiments, the compounds of the present invention are represented by Formula 5:

[0107] wherein X1 is selected from the group consisting of O, S and NH; and wherein R, R3 and n are as described above.

[0108] In some embodiments, the compounds of the present invention are represented by any of the following:

[0109]

[0110] wherein R, R3, n, and X1 are as described herein; and wherein R4 is as described above. In some embodiments, R4 is hydrogen or C1-C10 alkyl. In some embodiments, R4 is hydrogen.

[0111] In some embodiments, compounds of the invention are represented by Formula 4.1:

[0112] Wherein n is between 0 and 5; each R3 represents independently wherein A represents an optionally substituted aliphatic (C3-C20) ring, an optionally substituted aromatic (C5-C20) ring, or H; and R4 represents a substituent independently comprising hydrogen, C1-C10 alkyl, C1-C10 branched alkyl, substituted C1-C10 alkyl, halo, nitro, hydroxyl, thiol, amino, cyano, and carboxyl derivatives, or any combination thereof. In some embodiments, each X is independently selected from the group consisting of -N-, -NH, -O-, and -S-.

[0113] In some embodiments, the compounds of the present invention are or include:

[0114] It is also referred to herein as Compound 3, and optionally includes any salt or any derivative thereof.

[0115] In some embodiments, the compounds of the present invention are represented by any of the following:

[0116]

[0117] Or it can be expressed by Formula 7C:

[0118] wherein R4, X2, A, X1 and n are as described above, and wherein represents a single bond or a double bond. In one embodiment, the compounds of the present invention are represented by any one of Formulae 7A to 7C, wherein each X2 is independently selected from the group consisting of a methylene group, a heteroatom, an alkyl group, a halide group, an alkoxy group, a hydroxyl group, an amino group, a thioalkoxy group, a sulfhydryl group, a cyano group, a carboxylic acid derivative, a nitro group, a guanidine group, a heteroatom, an aryl group, a heteroaryl group, a benzyl group, an alkylaryl group, a cycloalkyl group, a heterocyclyl group, a bond, and hydrogen, or any combination thereof, and wherein each X1 is O. In some embodiments, R4 is hydrogen or a C1-C10 alkyl group.

[0119] In some embodiments, the compounds of the present invention are represented by Formula 8A:

[0120] Or it can be expressed by formula 8B:

[0121] Or it can be expressed by formula 8C:

[0122] wherein R4, X2, A, X1 and n are as described above, and wherein Indicates a single bond or a double bond.

[0123] In some embodiments, X1 is oxygen. In some embodiments, each X2 is independently selected from methylene, -N-, -NH, -O-, and -S-.

[0124] In some embodiments, the compounds of the present invention are represented by any one of Formulas 9A to 9F:

[0125] wherein R4, R3, X2 and A are as described above.

[0126] In some embodiments, the compounds of the present invention are represented by Formula 9G:

[0127] wherein R4, R' and X2 are as described above, and wherein R4' is C1-C10 alkyl or absent. In some embodiments, the compound of the present invention is represented by Formula 9G, and X2 is methylene or N.

[0128] In some embodiments, the compounds of the present invention are represented by Formula 6D:

[0129] wherein R′ and n are as described above; wherein X is CH or N; and wherein each A independently represents a (C3-C20)cycloalkyl, a (C3-C20)heterocyclyl (optionally including an unsaturated bond), an aryl or a heteroaryl group, and wherein at least one A is a (C3-C20)heterocyclyl or heteroaryl group. In some embodiments, each A is optionally replaced by one or more R' including: (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, -NO2, -CN, -OH, -CONH2, -CONR"2, -CNNR"2, -CSNR"2, -CONH-OH, -CONH-NH2, -NHCOR", -NHCSR", -NHCNR", -NC(=O)OR", -NC(=O)NR", -NC(=S)OR", -NC(=S)NR", -SO2R", -SOR", -SR", -SO2OR", -SON(R)2, -NHNR2, -NNR, C1-C 10 Haloalkyl, optionally substituted C1-C 10 Alkyl, -NH2, -NH(C1-C 10 Alkyl), -N(C1-C 10 Alkyl)2, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, hydroxy (C1-C 10 Alkyl), hydroxyl (C1-C 10 Alkoxy), alkoxy (C1-C 10 Alkyl), alkoxy (C1-C 10 Alkoxy), C1-C 10 Alkyl-NR"2, C1-C10 Alkyl-SR, -CONH(C1-C 10 Alkyl), -CON(C1-C 10 alkyl)2, -CO2H, -CO2R", -OCOR", -OCOR", -OC(=O)OR", -OC(=O)NR", -OC(=S)OR", -OC(=S)NR", including any combination thereof.

[0130] In some embodiments, the compounds of the present invention are represented by Formula 6E:

[0131] wherein X, n, and R' are as described herein, wherein X' is N or CH, and at least one X' is N. In some embodiments, both X' are N.

[0132] In some embodiments, the compound of the present invention is any of the following:

[0133]

[0134] including any salts and / or any derivatives thereof.

[0135] In some embodiments, the compound of the present invention is any of the following:

[0136]

[0137] including any salts and / or any derivatives thereof.

[0138] As used herein, the term "stereoisomer" refers to an enantiomer or diastereomer of a compound.

[0139] In some embodiments, the term "derivative" refers to: a prodrug of a compound, such as an ester; a tautomer of a compound, such as a keto-enol tautomer, an imine-enamine tautomer, an amide-iminoalcohol tautomer, including any combination thereof. In some embodiments, the term "derivative" refers to a compound substituted with one or more (e.g., 2, 3, 4, or 5) substituents, optionally wherein any one of the substituents is independently R', wherein R' is as described herein.

[0140] In some embodiments, provided herein are compositions comprising one or more compounds of the invention, including any salt (e.g., a pharmaceutically acceptable salt), any tautomer, and / or any stereoisomer thereof. In some embodiments, the compound as described above is the sole active ingredient in a composition (e.g., a pharmaceutical composition) of the invention.

[0141] In some embodiments, the composition of the present invention is a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the composition of the present invention is a pharmaceutical composition comprising at least one compound of the present invention as a first active ingredient and additional active ingredients.

[0142] In some embodiments, the pharmaceutical composition is in the form of a combination of parts or a kit.In some embodiments, the pharmaceutical composition of the present invention is used as a medicament.

[0143] Treatment

[0144] In another aspect, a method for inhibiting or reducing ApoL1-associated cytotoxicity in a subject in need thereof is provided, comprising administering to the subject a pharmaceutical composition or compound of the present invention. In some embodiments, the administration is by oral administration, systemic administration, or a combination thereof.

[0145] In some embodiments, the methods are used to prevent or treat a disease or condition associated with ApoL1. In some embodiments, the methods are used to prevent or treat a disease or condition associated with expression of a mutant allele of ApoL1 in a subject. In some embodiments, the methods are used to prevent or treat a disease or condition associated with overexpression of ApoL1 (mutant and / or wild-type) in a subject. In some embodiments, overexpression comprises increased intracellular concentration of ApoL1.

[0146] In some embodiments, ApoL1-related cytotoxicity includes ApoL1-induced endolysosomal disorder, ApoL1-induced mitochondrial dysfunction (such as by reducing mitochondrial respiration rate), ApoL1-induced increased potassium efflux, inflammasome activation, protein aggregation, protein-protein interaction, unfolded protein response, pyroptosis, necroptosis, ferroptosis, autophagy inhibition, or any combination thereof.

[0147] In some embodiments, ApoL1 is an ApoL1 mutant (eg, ApoL1 G1 and / or ApoL1 G2). The sequences of ApoL1 G1 / G2 mutant alleles are known in the art.

[0148] In some embodiments, the methods of the present invention include the steps of determining whether the expression level of at least one ApoL1 gene in a sample obtained or derived from a subject is increased (e.g., at least 10%, at least 50%, at least 100%, at least 200%, at least 300%, at least 1000%, including any range therebetween) above a predetermined threshold; and administering a therapeutically effective amount of a compound of the present invention to a subject determined to have an increased expression level of at least one ApoL1 gene above the predetermined threshold, thereby treating an ApoL1-related disease or condition in the subject. In some embodiments, the ApoL1-related disease or condition is or includes a disease or condition associated with overexpression of an ApoL1 gene in the subject. In some embodiments, the ApoL1 gene is a wild-type gene or a mutant gene (G1 and / or G2).

[0149] In some embodiments, the methods of the present invention comprise: determining a G1 mutation (S 342 >G and / or I 384 >M) or G2 mutation (e.g., 6 bp deletion N388del:Y389del), or both, are present in the ApoL1 gene of cells (e.g., kidney cells) of a subject; and administering to the subject determined to have cells comprising the G1 and / or G2 mutations in the ApoL1 gene, a therapeutically effective amount of a compound of the present invention, thereby treating a disease or condition associated with ApoL1 in the subject. In some embodiments, the ApoL1-associated disease or condition is or includes a disease or condition associated with the expression of an ApoL1 mutant allele (e.g., G1 and / or G2) in a subject.

[0150] In some embodiments, the cell is a kidney cell (e.g., a podocyte) or a vascular cell (e.g., an endothelial cell). In some embodiments, the cell comprises a mutant ApoL1 allele, wherein the mutant ApoL1 is as described herein. In some embodiments, the cell is characterized by overexpression of ApoL1 (mutant and / or wild type). In some embodiments, the cell comprises an ApoL1 G1 mutant, an ApoL1 G1 mutant, or both. In some embodiments, the cell selectively expresses a single ApoL1 mutant (G1 or G2). In some embodiments, the cell expresses multiple ApoL1 mutants. In some embodiments, the ApoL1 wild type has a sequence identical to NCBI gene ID 8542.

[0151] In some embodiments, selective expression includes expression of at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% of a single ApoL1 mutant, wherein the percentage of expression relates to the fraction of the ApoL1 mutant in the total ApoL1 protein content.

[0152] In some embodiments, the methods of the present invention include selectively inhibiting or reducing ApoL1 G1-associated cytotoxicity. In some embodiments, the methods of the present invention include selectively inhibiting or reducing ApoL1 G2-associated cytotoxicity. In some embodiments, the methods of the present invention include inhibiting or reducing both ApoL1 G1 and ApoL1 G2-associated cytotoxicity.

[0153] In some embodiments, the method is used to prevent or treat a kidney disease or condition. In some embodiments, the method is used to prevent or treat an ApoL1-related kidney disease or condition. In some embodiments, an ApoL1-related kidney disease includes kidney disease due to hypertension, sickle cell nephropathy, focal segmental glomerulosclerosis (FSGS), primary non-monogenic FSGS, HIV-related nephropathy, lupus nephritis, end-stage renal disease (ESRD), diabetic ESRD, proteinuria, or any combination thereof. In some embodiments, the method is used to prevent or treat an ApoL1-related cardiovascular disease. In some embodiments, ApoL1 is an ApoL1 mutant (such as ApoL1 G1 and / or ApoL1 G2).

[0154] In some embodiments, the method comprises administering the pharmaceutical composition of the present invention at least once, at least twice, at least three times, at least four times, at least five times, at least seven times, or at least ten times daily, or any value or range therebetween. Each possibility represents a separate embodiment of the present invention. In some embodiments, the method comprises administering the composition or combination of the present invention 1-2 times daily, 1-3 times daily, 1-4 times daily, 1-5 times daily, 1-7 times daily, 2-3 times daily, 2-4 times daily, 2-5 times daily, 3-4 times daily, 3-5 times daily, or 5-7 times daily. Each possibility represents a separate embodiment of the present invention.

[0155] In some embodiments, the subject is a mammal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a farm animal. In some embodiments, the subject is a human subject.

[0156] In certain embodiments, the compositions of the present invention are administered in a safe and effective amount for treatment. As used herein, the term "safe and effective amount" refers to an amount of a component that is commensurate with a reasonable benefit / risk ratio and is sufficient to produce a desired therapeutic response when used in the manner described herein without producing excessive adverse side effects (including but not limited to toxicity, such as calcium toxicity, irritation, or allergic reactions). The actual amount administered and the rate and time course of administration as target cells will depend on the nature and severity of the condition being treated. Decisions on treatment prescriptions, such as dosage and timing, are within the responsibility of a general practitioner or specialist, and are generally considered to include the condition to be treated, the condition of the individual patient, the delivery site, the method of administration, and other factors known to the practitioner. Examples of techniques and protocols can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, Philadelphia, Pennsylvania (2005).

[0157] In some embodiments, the effective amount or dosage of the active ingredient can be estimated initially from in vitro assays. In one embodiment, a dose can be formulated in animal models, and such information can be used to more accurately determine useful doses in humans.

[0158] In one embodiment, the toxicity and therapeutic efficacy of the active ingredients described herein can be determined in vitro, in cell culture or in experimental animals by standard pharmaceutical procedures. In one embodiment, the data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a dosage range for humans. In one embodiment, the dosage can vary depending on the dosage form used and the route of administration utilized. In one embodiment, individual physicians can select the exact formulation, route of administration, and dosage based on the patient's condition. [See, for example, Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th ed., McGraw-Hill / Education, New York City, NY (2017)].

[0159] In some embodiments, the subject has a disease or disorder selected from the group consisting of kidney disease due to hypertension, sickle cell nephropathy and focal segmental glomerulosclerosis (FSGS), primary non-monogenic FSGS, HIV-associated nephropathy, lupus nephritis, ApoL1-associated cardiovascular end-stage renal disease (ESRD), diabetic ESRD, proteinuria, or any combination thereof.

[0160] In some embodiments, the subject has an ApoL1-associated cardiovascular disease or condition. In some embodiments, the subject has a renal disease or condition. In some embodiments, the subject has a renal disease or condition characterized by cells expressing at least one ApoL1 mutant. In some embodiments, the ApoL1 mutant is a translation product of a mutant ApoL1 gene. In some embodiments, the mutant ApoL1 gene comprises an ApoL1G1 and / or ApoL1G2 mutation.

[0161] In some embodiments, reducing ApoL1 cytotoxicity comprises reducing cell death (e.g., by apoptosis or cell stress, or by protein interactions or self-aggregation or aggregate formation) by at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99%, including any values ​​therebetween. In some embodiments, the compounds of the invention significantly reduce the death rate of cells expressing ApoL1 mutants, as shown in FIG1 .

[0162] In some embodiments, the compounds of the present invention are substantially inactive against cells expressing a wild-type ApoL1 gene. In some embodiments, the methods are used to inhibit the enzymatic activity of an ApoL1 mutant.

[0163] In some embodiments, the compounds of the present invention have increased affinity for an ApoL1 mutant as described herein compared to wild-type ApoL1.

[0164] In some embodiments, the compounds of the present invention enhance cell viability in cells expressing at least one ApoL1 mutant. In some embodiments, cell viability is enhanced by at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 30-fold, at least 30-fold, at least 50-fold, at least 80-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, at least 700-fold, at least 1000-fold, at least 10,000-fold, at least 50,000-fold, or at least 100,000-fold compared to untreated cells (as represented in FIG1 ). In some embodiments, the compounds of the present invention enhance the viability of cells expressing at least one ApoL1 mutant in a dose-dependent manner (e.g., at concentrations between 0.2 μM and 10 μM).

[0165] In some embodiments, the compounds of the invention are substantially non-toxic at a concentration of less than 15 μM, less than 12 μM, less than 11 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 6 μM, less than 5 μM, less than 3 μM, less than 1 μM, and any range or value therebetween.

[0166] In some embodiments, the compounds of the invention are substantially non-toxic at concentrations between 0.001 μM and 15 μM, between 0.001 μM and 1 μM, between 1 μM and 5 μM, between 5 μM and 10 μM, between 10 μM and 12 μM, between 12 μM and 15 μM, including any range or value therebetween. In some embodiments, substantially includes less than 20%, less than 17%, less than 15%, less than 13%, less than 10%, less than 8%, less than 5% cell death, including any range or value therebetween.

[0167] In some embodiments, the ApoL1 gene mutation includes an ApoL1 G1 point mutation (S342G and / or I384M) and / or an ApoL1 G2 deletion mutation (Δ388N389Y). In some embodiments, the ApoL1 gene mutation is associated with resistance of cells expressing the ApoL1 mutant to trypanosome infection.

[0168] On the other hand, there is provided a method for preventing or treating a proliferative disease, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition or compound of the present invention. In some embodiments, administration is by oral administration, topical administration, systemic administration, or a combination thereof. In some embodiments, administration is as described herein. In some embodiments, the method is used to reduce cancer cell viability and / or inhibit its proliferation. In some embodiments, the reduction is a reduction of at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 97%, at least 99% cell viability (such as by apoptosis or cell stress, or by protein interactions or self-aggregation or the generation of aggregates, etc.).

[0169] In some embodiments, the subject has a disease or condition selected from the group consisting of brain cancer, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, liver cancer, glioblastoma, various forms of breast cancer, head cancer, neck cancer, esophageal cancer, prostate cancer, colorectal cancer, lung cancer, renal cancer, kidney cancer, ovarian cancer, gynecological cancer, thyroid cancer, non-small cell lung cancer (NSCLC), refractory ovarian cancer, EGFR mutant-associated cancer, and head and neck cancer, or any combination thereof.

[0170] carrier

[0171] In some embodiments, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable salt comprises a compound of the present invention and a pharmaceutically acceptable anion. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present invention as an active ingredient. In some embodiments, the compound of the present invention is the sole active ingredient in the pharmaceutical composition of the present invention.

[0172] Non-limiting examples of pharmaceutically acceptable anions include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, carbonate, halides (such as bromide, chloride, iodide, and fluoride), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, fumarate, gluconate, and lactate, or any combination thereof.

[0173] For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0174] In some embodiments, the pharmaceutical compositions described herein are topical compositions. In some embodiments, the pharmaceutical compositions are oral compositions. In some embodiments, the pharmaceutical compositions are injectable compositions. In some embodiments, the pharmaceutical compositions are for systemic use.

[0175] In some embodiments, the pharmaceutical composition is any one of an emulsion, liquid solution, gel, paste, suspension, dispersion, ointment, cream, or foam.

[0176] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered. Such carriers can be sterile liquids, such as water-based and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc., polyethylene glycols, glycerol, propylene glycol or other synthetic solvents.

[0177] Other non-limiting examples of carriers include, but are not limited to, terpenes derived from Cannabis, or total terpenes extracted from the Cannabis plant, terpenes from coffee or cocoa, mint extract, eucalyptus extract, citrus extract, tobacco extract, fennel extract, any plant oil, peppermint oil, d-limonene, b-myrcene, a-pinene, linalool, anethole, a-bisabolol, camphor, b-caryophyllene and caryophyllene oxide, 1,8-cineole, citral, citronella oil, delta-3-carene, farnesol, geraniol, indomethacin, isopulegol, linalool, uranyl acetate, b-myrcene, myrcenol, l-menthol, menthone, menthol and neomenthol, oridonin, a-pinene, diclofenac, nepafenac, bromfenac, phytol, terpineol, pinen-4-ol, thymol, and thymoquinone. Those skilled in the art will appreciate that the particular carrier employed within the pharmaceutical compositions of the present invention may vary depending on the route of administration.

[0178] In some embodiments, the carrier improves the stability of the active ingredient in a living organism. In some embodiments, the carrier improves the stability of the active ingredient in a pharmaceutical composition. In some embodiments, the carrier enhances the bioavailability of the active ingredient.

[0179] Water can be employed as a carrier, for example, when the active ingredient is sufficiently water-soluble for intravenous administration. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

[0180] In some embodiments, the carrier is a liquid carrier. In some embodiments, the carrier is an aqueous carrier.

[0181] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. If desired, the composition may also contain a small amount of a wetting agent or emulsifier, or a pH buffer such as acetate, citrate, or phosphate. Antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; and agents for regulating tonicity such as sodium chloride or dextrose are also contemplated. The carrier may comprise a total of 0.1% to 99.99999% by weight of the composition or pharmaceutical composition presented herein.

[0182] In some embodiments, the pharmaceutical composition comprises any of the active ingredients incorporated into or on a particulate formulation of a polymer compound such as polylactic acid, polyglycolic acid, a hydrogel, or incorporated into a liposome, microemulsion, micelle, unilamellar or multilamellar vesicle, erythrocyte ghost, or spheroplast. Such compositions can affect the physical state, solubility, stability, in vivo release rate, and in vivo clearance rate.

[0183] In some embodiments, the pharmaceutical composition is a liquid at a temperature of 15°C to 45°C. In some embodiments, the pharmaceutical composition is a solid at a temperature of 15°C to 45°C. In some embodiments, the pharmaceutical composition is a semi-liquid at a temperature of 15°C to 45°C. It should be understood that the term "semi-liquid" is intended to mean a material that can flow under pressure and / or shear forces. In some embodiments, semi-liquid compositions include creams, ointments, gel-like materials, and other similar materials. In some embodiments, the pharmaceutical composition is a semi-liquid composition characterized by a viscosity in the range of 31,000-800,000 cps.

[0184] Non-limiting examples of carriers for pharmaceutical compositions in the form of creams include, but are not limited to, nonionic surfactants (e.g., glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, lanolin alcohol, lecithin, mono- and diglycerides, poloxamers, polyoxyethylene 50 stearate and sorbitan trioleate, stearic acid), anionic surfactants (e.g., pharmaceutically acceptable salts of fatty acids such as stearic acid, oleic acid, palmitic acid, and lauric acid), cationic surfactants (e.g., pharmaceutically acceptable quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride), or any combination thereof.

[0185] In some embodiments, pharmaceutical compositions in the form of a cream further include a thickening agent.

[0186] Non-limiting examples of thickening agents include, but are not limited to, microcrystalline cellulose, starch, modified starch, gum tragacanth, gelatin, and polymeric thickeners (eg, polyvinylpyrrolidone), or any combination thereof.

[0187] In some embodiments, the pharmaceutical composition comprising the compound of the present invention is in unit dosage form. In some embodiments, the pharmaceutical composition is prepared by any of the methods well known in the pharmaceutical art. In some embodiments, the unit dosage form is in the form of a tablet, capsule, lozenge, wafer, mini-tablet, ampoule, vial, or pre-filled syringe.

[0188] In addition, in vitro assays can be optionally used to help identify the optimal dose range. The precise dosage used in the formulation will also depend on the nature of the route of administration and the disease or illness, and should be determined according to the practitioner's judgment and the condition of each patient. The effective dose can be inferred from the dose-response curve derived from an in vitro or in vivo animal model test bioassay or system. In certain embodiments, the effective dose is as described above.

[0189] In another embodiment, the pharmaceutical composition of the present invention is administered in any conventional oral, parenteral or transdermal dosage form.

[0190] As used herein, the terms "administering," "administration," and like terms refer to any method within good medical practice for delivering a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.

[0191] In certain embodiments, the pharmaceutical composition is administered by oral (i.e., enteral), rectal, vaginal, topical, nasal, ophthalmic, transdermal, subcutaneous, intramuscular, intraperitoneal or intravenous administration. The administration route of the pharmaceutical composition will depend on the disease or condition to be treated. Suitable administration routes include, but are not limited to, parenteral injection, for example, intradermal, intravenous, intramuscular, intralesional, subcutaneous, intrathecal and any other injection mode known in the art. In addition, it may be desirable to introduce the pharmaceutical composition of the present invention by any suitable route, including intraventricular and intrathecal injections; intraventricular injections can be promoted by, for example, an intraventricular catheter attached to a container. Pulmonary administration can also be employed, for example, by using an inhaler or a nebulizer.

[0192] In some embodiments, the pharmaceutical composition is in the form of, for example, but not limited to, an ointment, cream, gel, paste, foam, aerosol, suppository, pad, or gel stick.

[0193] In some embodiments, for oral use, the pharmaceutical composition is in the form of a tablet or capsule, which may contain any of the following ingredients or compounds with similar properties: a binder such as microcrystalline cellulose, tragacanth gum, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; or a glidant such as colloidal silicon dioxide. When the dosage unit form is a capsule, it may contain a liquid carrier such as a fatty oil in addition to the above-mentioned types of materials. In addition, the dosage unit form may contain various other materials that modify the physical form of the dosage unit, such as a coating of sugar, shellac, or other enteric solvents. In some embodiments, the tablets of the present invention are further coated with a film. In some embodiments, the oral administration of the pharmaceutical composition or kit is in the form of a drinkable liquid. In some embodiments, the oral administration of the pharmaceutical composition or kit is in the form of an edible product.

[0194] For the purpose of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, may be employed. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes.

[0195] In some embodiments, the subject is a mammal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a rodent. In some embodiments, the subject is a farm animal. In some embodiments, the subject is a human subject.

[0196] In some embodiments, compositions comprising a formulation of the invention formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0197] In some embodiments, the compositions of the present invention are present in a package or dispenser device, such as an FDA-approved test kit containing one or more unit dosage forms containing the active ingredient. In some embodiments, the packaging comprises, for example, metal or plastic foil, such as a blister pack. In some embodiments, the package or dispenser device is accompanied by instructions for administration. In some embodiments, the package or dispenser device is accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting the agency's approval of the composition or form of administration for human or veterinary use. In some embodiments, such notice is labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert.

[0198] definition

[0199] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight and branched chain groups. Preferably, the alkyl group has 1 to 10 carbon atoms, and more preferably 1-6 carbon atoms (or C1-C6 alkyl). Thus, a short alkyl group has 20 or fewer backbone carbons. The alkyl group may be substituted or unsubstituted, as defined herein.

[0200] As used herein, the term "alkyl" also encompasses saturated or unsaturated hydrocarbons, and therefore, this term further encompasses alkenyl and alkynyl. As used herein, the term "C1-C6 alkyl" comprising any C1-C6 alkyl related compound refers to any straight or branched alkyl chain comprising between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6 carbon atoms (including any range therebetween). In certain embodiments, C1-C6 alkyl includes any one of the following: methyl, ethyl, propyl, butyl, amyl, isopentyl, hexyl and tert-butyl or any combination thereof. In certain embodiments, C1-C6 alkyl as described herein further includes an unsaturated bond, wherein the unsaturated bond is located at the 1st, 2nd, 3rd, 4th, 5th or 6th position of the C1-C6 alkyl.

[0201] As used herein, the term "C1-C6 alkyl" includes any C1-C6 alkyl related compound. 10 "Alkyl" refers to any straight or branched alkyl chain comprising between 1 and 6, between 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, between 5 and 6, between 6 and 8, between 8 and 10 carbon atoms, including any range therebetween. In some embodiments, C1-C 10 Alkyl groups include any of methyl, ethyl, propyl, butyl, pentyl, isopentyl, hexyl, nonyl, decyl, ethenyl, propenyl, butenyl, and tert-butyl, or any combination thereof, wherein each alkyl group is optionally substituted with one or more substituents as described herein.

[0202] In some embodiments, C1-C as described herein 10 The alkyl group further includes an unsaturated bond, wherein the unsaturated bond is located between C1 and C 10 at the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th or 10th position of the alkyl group.

[0203] The term "alkenyl" describes an unsaturated alkyl group as defined herein having at least two carbon atoms and at least one carbon-carbon double bond. As described above, an alkenyl group may be substituted with one or more substituents or may be unsubstituted.

[0204] As defined herein, the term "alkynyl" is an unsaturated alkyl group having at least two carbon atoms and at least one carbon-carbon triple bond. As described above, an alkynyl group may be substituted with one or more substituents or may be unsubstituted.

[0205] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (i.e., a ring that shares adjacent pairs of carbon atoms) in which one or more of the rings does not have a completely conjugated pi-electron system. As indicated herein, a cycloalkyl group may be substituted or unsubstituted. In some embodiments, the term "cycloalkyl" refers to a C3-C10 cyclic ring. In some embodiments, the term "cycloalkyl" refers to a C3-C10 cyclic ring that includes 1, 2, 3, or 4 heteroatoms (e.g., N, NH, O, or S). (C3-C 10 ) ring refers to an optionally substituted C3, C4, C5, C6, C7, C8, C9 or C10 ring. In some embodiments, (C3-C 10 ) ring includes optionally substituted cyclopropane, cyclobutene, cyclopentane, cyclohexane or cycloheptane.

[0206] In some embodiments, the term "cycloalkyl" refers to a group containing a non-aromatic ring, wherein each atom in the atoms forming the ring is a carbon atom. A cycloalkyl group can be formed by three, four, five, six, seven, eight, nine or more than nine carbon atoms. A cycloalkyl group can be optionally substituted. In certain embodiments, a cycloalkyl group contains one or more unsaturated bonds. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane and cycloheptene.

[0207] In some embodiments, the term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a completely conjugated π electron system. In some embodiments, the term "aryl" describes an aromatic (C6-C 12 ) ring. As indicated herein, aryl groups can be substituted or unsubstituted. In some embodiments, the term "(C6-C 12 ) ring" refers to an optionally substituted C6, C7, C8, C9, C10, C11 or C12 aromatic ring. In some embodiments, (C6-C 12) Aromatic ring refers to a bicyclic aryl or a bicyclic heteroaryl (e.g., a fused ring, a spirocycle, and a bicyclic ring). In some embodiments, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic system that does not contain ring heteroatoms. In the case where the system is not a monocyclic system, the term aryl includes a saturated form (perhydro form) or a partially unsaturated form (e.g., a dihydro form or a tetrahydro form) or a maximum unsaturated (non-aromatic) form for each additional ring. In some embodiments, the term aryl refers to a bicyclic radical in which two rings are aromatic and a bicyclic radical in which only one ring is aromatic. Examples of aryl include phenyl, naphthyl, anthracenyl, indanyl, 1,2-dihydro-naphthyl, 1,4-dihydronaphthyl, indenyl, 1,4-naphthoquinone and 1,2,3,4-tetrahydronaphthyl.

[0208] The aryl ring can be formed by three, four, five, six, seven, eight, nine or more carbon atoms. In some embodiments, aryl refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13- or 14-membered aromatic monocyclic, bicyclic or tricyclic ring system. In some embodiments, aryl refers to an aromatic C3-C9 ring. In some embodiments, aryl refers to an aromatic C4-C8 ring. Aryl can be optionally substituted.

[0209] As used herein, the term "bicyclic heteroaryl" refers to a (C6-C 12 ) bicyclic heteroaryl ring, wherein the bicyclic (C6-C 10 ) ring as described herein.

[0210] As used herein, the term "bicyclic aryl" refers to a (C6-C 12 ) bicyclic aryl ring, wherein the bicyclic (C6-C 12 ) ring as described herein.

[0211] As defined herein, the term "alkoxy" describes both O-alkyl and -O-cycloalkyl groups.

[0212] As defined herein, the term "aryloxy" describes an -O-aryl group.

[0213] Each of the alkyl, cycloalkyl, and aryl groups in the general formula herein may be substituted with one or more substituents, whereby each substituent group may independently be, for example, a halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxyl, amide, aryl, and aryloxy group, depending on the group being substituted and its position in the molecule. Additional substituents are also contemplated.

[0214] The term "haloalkyl" describes an alkyl group, as defined herein, that is further substituted with one or more halide ions.

[0215] The term "haloalkoxy" describes an alkoxy group, as defined herein, that is further substituted with one or more halide ions.

[0216] The term "hydroxyl" or "hydroxy" describes an -OH group.

[0217] The term "mercapto" or "sulfanyl" describes a -SH group.

[0218] The term "thioalkoxy" describes an -S-alkyl and -S-cycloalkyl group as defined herein.

[0219] The term "thioaryloxy" describes both -S-aryl and -S-heteroaryl groups as defined herein.

[0220] The term "amino" describes a -NR'R' group, where R' and R" are as described herein.

[0221] As used herein, the term "heterocycle" refers to a ring in which at least one atom forming the ring is a carbon atom and at least one atom forming the ring is a heteroatom. Heterocycle can be formed by three, four, five, six, seven, eight, nine or more than nine atoms. Any number of these atoms can be a heteroatom (that is, heterocycle can contain one, two, three, four, five, six, seven, eight, nine or more than nine heteroatoms, provided that at least one atom in the ring is a carbon atom). In this article, whenever the number of carbon atoms in the heterocycle is indicated (for example, C1-C6 heterocycle), at least one other atom (heteroatom) must be present in the ring. Names such as "C1-C6 heterocycle" only refer to the number of carbon atoms in the ring, and do not refer to the total number of atoms in the ring. It should be understood that heterocycle will have other heteroatoms in the ring. Names such as "4- to 6-membered heterocycle" refer to the total number of atoms that make up the ring (i.e., a four-membered ring, a five-membered ring, or a six-membered ring in which at least one atom is a carbon atom, at least one atom is a heteroatom, and the remaining two to four atoms are carbon atoms or heteroatoms). In a heterocycle containing two or more heteroatoms, the two or more heteroatoms may be the same or different from each other. The heterocycle may be optionally substituted. The binding to the heterocycle may be at a heteroatom or through a carbon atom. As used herein, the term "carbocycle" refers to a ring in which each of the atoms that form the ring is a carbon atom. The carbocycle may be formed of 3, 4, 5, 6, 7, 8, 9, or more than 9 carbon atoms. The carbocycle may be optionally substituted.

[0222] As used herein, the term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may all be identical to one another, or some or all of the two or more heteroatoms may each be different from the other heteroatoms.

[0223] As used herein, the term "bicyclic" refers to two rings, wherein the two rings are fused. Bicyclic includes, for example, decaline, pentalene, indene, naphthalene, azulene, heptalene, isobenzofuran, chromene, indolizine, isoindole, indole, indoline, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, pteridine, isochroman, chroman and various hydrogenated derivatives thereof. Bicyclic can be optionally substituted. Each ring is independently aromatic or non-aromatic. In certain embodiments, both rings are aromatic. In certain embodiments, both rings are non-aromatic. In certain embodiments, one ring is aromatic and one ring is non-aromatic.

[0224] As used herein, the term "aromatic" refers to a planar ring having a delocalized π electron system containing 4n+2π electrons, where n is an integer. An aromatic ring can be formed of five, six, seven, eight, nine or more than nine atoms. Aromatics can be optionally substituted. Examples of aromatic groups include, but are not limited to, phenyl, tetralinyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, indenyl and indanyl. The term aromatics includes, for example, a benzene-type group connected by one of the ring carbon atoms and optionally carrying one or more substituents selected from the group consisting of aryl, heteroaryl, cycloalkyl, non-aromatic heterocycle, halo, hydroxyl, amino, cyano, nitro, alkylamino, acyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6Alkylamino, alkylsulfenyl (alkylsulfenyl), alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl. In certain embodiments, the aromatic group is substituted at one or more of the para position, meta position and / or ortho position. Examples of substituted aromatic groups include but are not limited to phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxy-phenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyano-phenyl, 4-cyanophenyl, naphthyl, dimethylphenyl, hydroxynaphthyl, hydroxymethyl-phenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl and 4-(2-oxopyrrolidin-1-yl)phenyl.

[0225] The term "carboxy" or "carboxyl" describes a -C(O)OR' group where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon), or heterocyclyl (bonded through a ring carbon), as defined herein, or where R' is absent, e.g., carboxylate.

[0226] The term "carbonyl" describes a -C(O)R' group, where R' is as defined above.

[0227] The above terms also encompass the thio derivatives thereof (thiocarboxy and thiocarbonyl).

[0228] As used herein, the term "carboxylic acid derivative" encompasses carboxyl groups, amides, carbonyl groups, anhydrides, carbonates, and carbamates as described herein.

[0229] The term "thiocarbonyl" describes a -C(S)R' group, where R' is as defined above.

[0230] A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein.

[0231] A "sulfinyl" group describes a -S(O)R' group, where R' is as defined herein.

[0232] A "sulfonyl" or "sulfonate" group describes a -S(O)2R' group, where R' is as defined herein.

[0233] A "carbamoyl" or "carbamate" group describes a -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'.

[0234] A "nitro" group refers to a -NO2 group.

[0235] In some embodiments, the term "amide" refers to a chemical moiety having the formula -(R)nC(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. In certain embodiments, the amide can be an amino acid or a peptide.

[0236] As used herein, the term "amide" encompasses C-amides and N-amides.

[0237] The term "C-amide" describes a -C(O)NR'R" terminal group or a -C(O)NR'- linking group, as these phrases are defined above, where R' and R" are as defined herein.

[0238] The term "N-amide" describes a -NR"C(O)R' terminal group or a -NR'C(O)- linking group, as these phrases are defined above, where R' and R" are as defined herein.

[0239] As used herein, the term "carboxylic acid derivative" encompasses carboxyl groups, amides, carbonyl groups, anhydrides, carbonates, and carbamates.

[0240] A "cyano" or "nitrile" group refers to a -CN group.

[0241] The term "azo" or "diazo" describes an -N=NR' terminal group or an -N=N- linking group, as those phrases are defined above, where R' is as defined above.

[0242] The term "guanidine" describes a -R'NC(N)NR"R"' terminal group or a -R'NC(N)NR"- linking group, as these phrases are defined above, where R', R", and R'" are as defined herein.

[0243] As used herein, the term "alkyl sulfate" refers to an alkyl group as defined herein, further substituted by one or more sulfate groups (-OS(=O)2OH and / or (-OS(=O)2O - )replace.

[0244] As used herein, the term "azide" refers to a -N3 group.

[0245] The term "sulfonamide" refers to a -S(O)2NR'R" group, where R' and R" are as defined herein.

[0246] The term "phosphono" or "phosphonate" describes a -OP(O)-(OR')2 group, where R' is as defined above.

[0247] The term "phosphinyl" describes a -PR'R" group, where R' and R" are as defined above.

[0248] As defined herein, the term "alkylaryl" describes an alkyl group substituted with an aryl group as described herein. An exemplary alkylaryl group is benzyl.

[0249] As used herein, the term "heteroaryl" refers to an aromatic ring in which at least one of the atoms forming the aromatic ring is a heteroatom. The heteroaryl ring can be formed by three, four, five, six, seven, eight, nine, and more than nine atoms. The heteroaryl group may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 2-aryl groups containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms, or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and substituted aromatic C 2-aryl groups and benzo and pyrrofused derivatives thereof, for example, connected via one of the ring-forming carbon atoms. 3-8 In certain embodiments, the heteroaryl group is selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0250] In some embodiments, heteroaryl is selected from pyrrolyl, furanyl (furanyl or furyl), thiophenyl (thienyl or thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridinyl or pyridyl) yl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienothiphenyl, 1,8-naphthyridinyl, other naphthyridinyl, pteridinyl or phenothiazinyl. When the heteroaryl group contains more than one ring, each additional ring is saturated (perhydro form) or partially unsaturated (e.g., dihydro form or tetrahydro form) or maximally unsaturated (non-aromatic) form. The term heteroaryl therefore includes bicyclic groups in which both rings are aromatic as well as bicyclic groups in which only one ring is aromatic. Examples of such heteroaryl groups include 3H-indolinyl, 2(1H)-quinolinyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolinyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromanyl, 3,4-dihydroiso-quinoxalinyl, 4-(3H)quinazoline, Keto, 4H-chromenyl, 4-chromanonyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo[g]isoquinolyl, 1,2,3,4-tetrahydro-benzo[g]isoquinolyl , chromanyl, isochromanonyl, 2,3-dihydrochromanyl, 1,4-benzo-dioxanyl, 1,2,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydro- oxazolyl, 1,4-naphthoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolinyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolinyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5,6,7-tetrahydro-benzoxazolyl, 1H-4-oxa-1,5-diaza-naphthalen-2-one, 1,3-dihydroimidazo-[4,5]-pyridin-2-one, 2,3-dihydro-1,4-dinaphtho-quinone, 2,3-dihydro-1H-pyrrolo[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthyridinyl, 1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indolyl, 1,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo-[3,4-b]indolyl, 1H-2,3,4,5-tetrahydro-aza[3,4-b]indolyl, 1H-2,3,4,5-tetrahydro-aza[4,3-b]indolyl, 1H-2,3,4,5-tetrahydro-aza[ 4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[2,7]-naphthyridinyl, 2,3-dihydro[1,4]dioxin[2,3-b]pyridinyl, 2,3-dihydro[1,4]dioxin[2,3-b]pyridinyl, 3,4-dihydro-2H-1-oxa[4,6]naphthyridinyl, 4,5,6,7- Tetrahydro-3H-imidazo-[4,5-c]pyridinyl, 6,7-dihydro[5,8]naphthyridinyl, 1,2,3,4-tetrahydro[1,5]-naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl, 1,2,3,4-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl or 1,2,3,4-tetrahydro[2,6]naphthyridinyl. In some embodiments, heteroaryl is optionally substituted. In one embodiment, one or more substituents are each independently selected from halo, hydroxy, amino, cyano, nitro, alkylamino, acyl, C, 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -Hydroxyalkyl, C 1-6 -aminoalkyl, C 1-6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl or trifluoromethyl.

[0251] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted furan derivatives, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, OC 1-6 -alkyl, C 1-6-alkyl, alkoxy-C 1-6 -alkyl and amino-C 1-6 -alkyl.

[0252] In some embodiments, the terms "heteroaryl" and "C5-C6 heteroaryl" are used interchangeably herein.

[0253] As used herein, the terms "halo" and "halide," referred to interchangeably herein, describe an atom of a halogen, ie, fluorine, chlorine, bromine, or iodine, which are also referred to herein as fluoride, chloride, bromide, and iodide.

[0254] The term "haloalkyl" describes an alkyl group as defined above that is further substituted with one or more halide ions.

[0255] As used herein, the term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and non-aromatic heterocycles), aromatics (e.g., aryl and heteroaryl), and non-aromatics (e.g., cycloalkyl and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system.

[0256] As used herein, the term "ring system" refers to two or more rings, wherein two or more of the rings are fused. The term "fused" refers to a structure in which two or more rings share one or more bonds.

[0257] The term "substituted" or the term "substituent" refers to 1, 2, 3, 4 or 5 substituents, each of which is independently selected from (C0-C6)alkyl-aryl, (C0-C6)alkyl-heteroaryl, (C0-C6)alkyl-(C3-C8)cycloalkyl, optionally substituted C3-C8 heterocyclyl, halogen, NO2, CN, OH, CONH2, CONR2, CNNR2, CSNR2, CONH-OH, CONH-NH2, NHCOR, NHCSR, NHCNR, -NC(=O)OR, -NC(=O)NR, -NC(=S)OR, -NC(=S)NR, S02R, SOR, -SR, S02OR, S02N(R)2, -N HNR2, -NNR, C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkylNR2, C1-C6 alkylSR, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)2, CO2H, CO2R, -OCOR, -OCOR, -OC(=O)OR, -OC(=O)NR, -OC(=S)OR, -OC(=S)NR, including any combination thereof.

[0258] Overview

[0259] Throughout this application, various embodiments of the present invention can be presented in range format. It should be understood that the description using range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention. Therefore, the description of a range should be considered to have all possible sub-ranges disclosed and individual numerical values ​​within the range. For example, a range description such as 1 to 6 should be considered to have specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within the range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0260] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integer) within the indicated range. The phrases "a range between" a first indicated numeral and a second indicated numeral and "a range from" a first indicated numeral to a second indicated numeral are used interchangeably herein and are meant to include the first and second indicated numerals and all fractions and integers therebetween.

[0261] As used herein, the term "substantially" refers to at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.9%, including any range or value therebetween. In some embodiments, the term "substantially" and the term "consisting essentially of" are used interchangeably herein.

[0262] In some embodiments, the terms "treatment" or "treating" a disease, disorder, or condition encompasses substantial alleviation of at least one symptom thereof, substantial reduction in severity, or inhibition of progression thereof, substantially as described herein. Treatment does not necessarily mean that the disease, disorder, or condition is completely cured. To be effective treatment, useful compositions herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, or improve the quality of life of the patient or subject.

[0263] As used herein, the term "prevention" of a disease, disorder, or condition encompasses the delay, prevention, containment, or inhibition of the onset of a disease, disorder, or condition. As used in accordance with the presently described subject matter, the term "prevention" relates to a preventive process in which a subject is exposed to the presently described active ingredients prior to the induction or onset of the disease / disorder process. This can be done in situations where an individual has a genetic pedigree that indicates a predisposition to prevent the occurrence of a disease / disorder. For example, this may be the case for an individual whose ancestors exhibited a susceptibility to certain types of inflammatory conditions.

[0264] The term "containment" is used to describe a condition in which the disease / disorder process has begun but overt symptoms of the condition have not yet materialized. Thus, an individual's cells may harbor a disease / disorder but external signs of the disease / disorder may not yet be clinically recognized. In either case, the term prevention may be used to encompass both prevention and containment.

[0265] In contrast, the term "treatment" refers to the clinical use of an active agent to combat an existing condition, clinical manifestation of which has been achieved in a patient.

[0266] In the discussion, unless otherwise indicated, adjectives such as "substantially" and "about" modifying conditions or relational characteristics of one or more features of an embodiment of the present invention are understood to mean that the conditions or characteristics are defined within a tolerance range acceptable for the operation of the embodiment for its intended application. Unless otherwise indicated, the word "or" in the specification and claims is considered to be inclusive rather than exclusive and means at least one or any combination of the items it combines.

[0267] It should be understood that the terms "a" and "an" as used herein above and elsewhere herein refer to "one or more" of the listed components. It will be clear to one of ordinary skill in the art that, unless otherwise specifically stated, the use of the singular encompasses the plural. Thus, the terms "a," "an," and "at least one" are used interchangeably in this application.

[0268] For a better understanding of the present teachings, and in no way limiting the scope of the present teachings, all numbers and other numerical values ​​expressing quantities, percentages or ratios used in the present specification and claims should be understood as being modified in all cases by the term "about", unless otherwise indicated. Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and the appended claims are approximate values, which may vary depending on the desired properties sought to be obtained. At the very least, each numerical parameter should at least be interpreted in light of the number of reported significant digits and by applying conventional rounding techniques.

[0269] In the description and claims of this application, each of the verbs "comprise," "include," and "have" and their cognates is used to indicate one or more objects of the verb, not necessarily a complete list of components, elements, or parts of the subject one or more of the verb.

[0270] Other terms as used herein are intended to be defined by their known meanings in the art.

[0271] As used herein, the term "or" is to be understood as inclusive unless explicitly stated or obvious from the context.

[0272] Throughout this specification and claims, the word "comprise" or variations such as "comprises" or "comprising" indicates the inclusion of any recited integer or group of integers but not the exclusion of any other integer or group of integers.

[0273] As used herein, the term "consists essentially of" or variations such as "consist essentially of" or "consisting essentially of" as used throughout the specification and claims indicate the inclusion of any recited integer or group of integers, and optionally the inclusion of any recited integer or group of integers that does not materially alter the basic or novel property of the specified method, structure, or composition.

[0274] As used herein, the terms "comprises," "comprising," "containing," "having," and the like may mean "includes," "including," and the like, and "consisting essentially of," or "consists essentially of" also have the meaning ascribed thereto in U.S. patent law and are open ended, allowing for additions beyond what is recited as long as the recited basic or novel features are not altered by additions beyond what is recited, but excluding prior art embodiments. In one embodiment, the terms "comprises," "comprising," and "having" are interchangeable with "consisting of."

[0275] Although the present invention has been described in conjunction with the specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. It is therefore intended to encompass all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0276] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety into this specification, to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

[0277] Examples

[0278] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the present invention in a non-limiting fashion.

[0279] Generally, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, and microbiological techniques. Such techniques are fully explained in the literature.

[0280] Materials and Methods

[0281] Compound 1 was purchased from MayBridge (Cat. No. HTS12305), and compounds 3 and 7 were purchased from ChemBridge (Cat. Nos. 7990186 and 37031742, respectively). Compound solutions were prepared by diluting stock solutions (10 mM in 100% DMSO) with water to obtain the desired concentrations before use.

[0282] ApoL1-G1 induced T-REx-293 stable cell line was generated by introducing Flag-tagged human G1ApoL1 variant DNA (with African genomic sequence background) into pcDNA4 / TO plasmid, which produced expression when doxycycline was added. Cells were cultured at 37°C in DMEM (Gibco, 41965-039) supplemented with 10% FBS, 1% penicillin-streptomycin.

[0283] In order to estimate the effect of compound 1, 3 and 7 on the cells induced by ApoL1, cell viability assay was performed as follows: cells were seeded at a density of 23K cells per well (96-well plate). Before inoculation, wells were coated with fibronectin (Biological Industries, 03-090-1-05) at 37°C for 1 hour. On the second day, cells were switched to the same but containing 1 ng / ml doxycycline (Sigma, D9891) with different concentrations of compound 1, 3 or 7 for 16 hours. The cells were then subjected to viability assay using CellTiter-Glo luminescent cell viability assay kit (Promega, G7570) according to the manufacturer's instructions. The luminescence of the plate was read using Infinite200PRO, which indicated a viable cell count.

[0284] Example 1

[0285] APOL1-G1-induced cell viability assay

[0286] The ApoL1-G1 variant was induced to produce toxicity in the T-REx-293 cell line by doxycycline. In order to identify potential inhibitors of ApoL1 toxicity, 200,000 chemical compounds were subjected to a cell-based high-throughput screening. The cells were incubated with a solution of the compound (at a concentration of 10 μM). After careful screening, three compounds (compounds 1, 3, and 7, whose chemical structures are described above) showed the highest cytoprotective effect without exhibiting significant cytotoxicity.

[0287] As shown in Figure 1, compounds 1, 3 and 7 showed a concentration-dependent increase in the viability of cells expressing ApoL1-G1 (orange bars). The blue bars represent the viability of cells expressing wild-type ApoL1. Additional compounds were tested to evaluate their cytoprotective effects.

[0288] Example 2

[0289] Inhibition of cell proliferation induced by exemplary compounds of the present invention

[0290] The present inventors performed cytotoxicity assays in order to evaluate the potential anti-proliferative effects of exemplary compounds of the present invention.

[0291] T-REx-293 cells were seeded on fibronectin in 96-well plates at a density of 25K cells / well and grown in DMEM containing 10% FBS, 1% P / S culture medium. The culture medium after 24 hours of inoculation was changed into fresh culture medium containing the test compound (KS-1, KS-2 or KS-8) at a concentration of 5-10 μM. Untreated cells were used as negative controls. After 16 hours, a plate of cells was taken for cell viability testing using Cell-Titer Glo reagent (Promega). The cells on another plate were imaged using the Incucyte ZOOM system.

[0292] Exemplary compounds of the present invention that were tested are as follows:

[0293]

[0294] The results are summarized in Figure 2 (for 10 μM concentration). Figure 2 As can be seen in the graph shown in Figure , for cells grown in the presence of compounds KS-1, KS-2, and KS-8, cell counts, as measured by luminescence signal (RLU), were lower. Thus, the tested compounds significantly reduced the viability and / or proliferation rate of immortalized cells. It can be hypothesized that the compounds of the present invention can be used as effective antiproliferative agents.

[0295] Although the present invention has been described in detail, it will be appreciated by those skilled in the art that many variations and modifications may be made. Therefore, the present invention should not be construed as being limited to the specifically described embodiments, and the scope and concept of the present invention will be more readily understood by reference to the following claims.

Claims

1. Use of a compound, a tautomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ApoL1-related kidney disease, wherein the compound is represented by the following formula: (Formula 4.1), (Equation 1.3), or (Formula 1D); in: Each R is independently selected from a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted phenyl group, and a substituted or unsubstituted 5-6 membered heteroaryl group; Each R1 is independently selected from substituted or unsubstituted C1-C3 alkyl; R3 does not exist; R4 is hydrogen; Each R' is independently selected from halogen and C1-C3 alkyl, or R' is absent; Each X is independently N, NH or CH; represents a single bond or a double bond; and Each n is 0 or 1.

2. The use according to claim 1, wherein the compound of formula 1D is its tautomers or a pharmaceutically acceptable salt of any of the foregoing.

3. The use according to claim 1, wherein the compound of formula 4.1 is its tautomers or a pharmaceutically acceptable salt of any of the foregoing.

4. The use according to claim 1, wherein the compound of formula 1.3 is its tautomers or a pharmaceutically acceptable salt of any of the foregoing.

5. A compound selected from: ， its tautomers and pharmaceutically acceptable salts of any of the foregoing.

6. A pharmaceutical composition comprising: The compound, tautomer or pharmaceutically acceptable salt according to claim 5, and a pharmaceutically acceptable carrier.

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